Background/Purpose: The pain that accompanies rheumatoid arthritis and other chronic inflammatory conditions is difficult to manage. Although opioids provide potent analgesia, chronic opioid use is associated with tolerance and addiction. Recent studies have demonstrated functional interactions between chemokines and opioids in pain signaling pathways. Reported crosstalk and even heterodimerization between chemokine and opioid receptors led our group to develop bivalent compounds that can bind both types of receptors, with the goal of targeting opioids to sites of inflammation. MCC22 is novel bivalent compound comprising a CCR5 antagonist and a mu opioid receptor agonist, connected by a 22-atom linker. We evaluated the efficacy of MCC22 in the K/B.g7 T cell receptor transgenic mouse model of inflammatory arthritis.

Methods: MCC22 or morphine was administered intraperitoneally at varying doses to arthritic K/B.g7 mice or non-arthritic control mice. Mechanical pain hypersensitivity was measured each day before (baseline) and after drug administration, using the electronic von Frey test. The potency of MCC22 relative to morphine was calculated. Functional readouts of pain included grip strength and nesting behavior. A separate dosing regimen was used to determine whether the drugs induced pharmacologic tolerance.

Results: MCC22 provided ~3000-fold more potent analgesia than morphine in this model of inflammatory arthritis. Daily treatment with MCC22 also led to a cumulative analgesic effect, reducing the daily baseline pain level. MCC22 produced no observable analgesic effect in non-arthritic control mice. Importantly, repeated administration of MCC22 did not induce pharmacologic tolerance, whereas a similar regimen of morphine did. Both grip strength and nesting behaviors improved among arthritic mice treated with MCC22. Ankle thickness and arthritis scores were not affected by MCC22 administration. The analgesic effect of MCC22 was abolished in K/B.g7 mice genetically lacking CCR5, demonstrating the receptor specificity of the pharmacophore.

Conclusion: MCC22 is a novel bivalent compound that relies on a CCR5 antagonist to deliver an opioid agonist to sites of inflammatory pain. Our findings demonstrate that MCC22 provides highly potent analgesia and improved functional outcomes in a model of inflammatory arthritis, without inducing typical opioid tolerance. These findings suggest that MCC22 or similar compounds could be used to treat the pain associated with inflammatory arthritis and related conditions, while minimizing the risks typically associated with chronic opioid use.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mcc22-a-novel-compound-that-targets-both-ccr5-and-mu-opioid-receptors-is-highly-effective-in-treating-inflammatory-arthritis-pain/